Therapeutic agent for renal failure

ABSTRACT

The present invention relates to a therapeutic agent for renal failure comprising, as an active ingredient, a 4,8-inter-m-phenylene prostaglandin I 2  derivative, and also relates to a method for treatment of renal failure using the same.

TECHNICAL FIELD

The present invention relates to a therapeutic agent for renal failurecomprising, as an active ingredient, a 4,8-inter-m-phenyleneprostaglandin I₂ derivative or a pharmacologically acceptable saltthereof.

BACKGROUND ART

Prostaglandins (PGs) are a class of naturally occurring compounds with awide variety of physiological activities, which have a common prostanoicacid skeleton. Naturally occurring PGs are classified into PGAS, PGBs,PGCs, PGDs, PGEs, PGFs, PGGs, PGHs, PGIs and PGJs according to thestructural characteristics of the 5-membered ring in the skeleton. It isand also classified into subclasses 1, 2, 3 and so on according to theansaturation and oxidation. Various synthetic analogues of these PGs areknown. Among these, PGI₂, which is a typical PGI derivative, is calledprostacycline (see Nature, vol. 268, p. 688, 1976). PGI₂ is known as asubstance having potent platelet aggregation inhibiting activity andperipheral vasodilator activity. Japanese Examined Patent ApplicationPublication Nos. 2-12226, 2-57548 and 1-53672 have described4,8-inter-m-phenylene PGI₂ derivatives, in which the exo-enol ethermoiety that is a structurally characteristic portion of PGI₂ isconverted to an inter-m-phenylene moiety to substantially improve theinstability of PGI₂. However, it has not yet recognized that suchderivatives have therapeutic activities on renal failure.

Renal failure is a condition characterized by decreased number offunctional nephrons, resulting in reduced excretion of nitrogenousmetabolic products and eventually causing the failure to maintainhomeostasis in the biological environment. Specifically, this can besaid to be a condition in which blood urea nitrogen (BUN) and creatininelevels are continuously increased. Renal failure is categorized into twoprimary types: acute renal failure in which the onset is abrupt andrecovery may occur; and chronic renal failure which is slowlyprogressive but irreversible.

Acute renal failure is primarily categorized into the following twotypes: oliguric acute renal failure which is frequently complicated bywater, electrolyte and acid-base imbalances and manifested by oliguriaor anuria; and non-oliguric acute renal failure in which decreasedurinary volume is not found.

Acute renal failure is also categorized into the following three typesaccording to its cause: 1) pronephric acute renal failure in whichreduction of renal blood flow occurs due to systemic hemodynamic changessuch as prerenal dehydration and shock, causing reduced glomerularfiltration rate; 2) renal acute renal failure which is induced byglomerular and tubular disorders such as acute tubular necrosis; and 3)postrenal acute renal failure which is caused by obstruction of theurinary tract, e.g., by a calculus. According to the clinicalmanifestations, it can also be categorized into oliguric, uretic andrecovery stages. In the treatment of acute renal failure, it isimportant to track down its cause and sufficiently perform systemiccontrol of the patient. Such treatment includes two major forms,conservative treatment and dialytic treatment. According to theconservative treatment, in the oliguric stage, excessive water drinkingis avoided and the amount of protein intake is restricted, whilesimultaneously supplying a sufficient amount of calories. In theoliguric stage, or when heart failure has occurred, then sodium intakeis restricted. In contrast, in the uretic stage, potassium intake isincreased. Generally in the oliguric stage, calcium intake isrestricted. In the case where BUN is 60 mg/dl or higher or rises by 30mg/dl or more per day or hyperkalemia or heart failure is found, then itis recommended to perform an early frequent dialysis.

Chronic renal failure is a condition in which gradual reduction in renalfunctions occurs due to a chronically progressive renal disease, inwhich the reduced renal functions are manifested as the insufficiency ofall functions for which the normal kidney is responsible. The causaldiseases of chronic renal failure are all of the nephropathic diseases,including primary renal diseases, nephropathy in systemic diseases,congenital renal diseases, renal infections, nephropathy induced by anynephrotoxic substance and obstructive urinary diseases. As seen in theclinical background of patients to whom dialysis has been introduced fortreatment of chronic renal failure, the primary causal diseases ofchronic renal failure may include chronic glomerulonephritis, diabeticnephropathy, chronic pyelonephritis, nephrosclerosis and cystic kidney.Among these, chronic glomerulonephritis and diabetic nephropathy make upa large proportion. The proportion of diabetic nephropathy as the causaldisease in the total cases, however, remarkably increases as the numberof diabetic patients rapidly increases in recent years.

As stated above, renal failure may be caused by various diseases.However, all types of renal failure have particular common clinicalmanifestations regardless of their causal diseases, such as lungcongestion and congestive heart failure associated with reduced urinaryvolume; neurological or mental complaints associated with advanceduremia; anemia caused by reduced production of erythropoietin in thekidney; electrolyte imbalance, such as hyponatremia and hyperkalemia;gastrointestinal complaints; defect of bone metabolism; and defect ofcarbohydrate metabolism.

For the treatment of chronic renal failure in the conservative stage,dietary therapy including a low-protein, high-calorie diet is basicallyemployed. In this case, it is required to restrict sodium chlorideintake and water intake and to use an antihypertensive agent to controlthe hypertention which may be a risk factor for exacerbation of renalfailure. However, such dietary therapy and the treatment with anantihypertensive agent as mentioned above produce unsatisfactoryeffects. Therefore, the number of patients who inevitably havehemodialysis goes on increasing year by year due to the manifestation ofuremic symptoms caused by the advanced disorders of renal functions. Inpatients with renal failure who have entered into dialysis, remarkableimprovement in the rate of prolongation of life has been achieved due tothe improved hemodialysis therapy in recent years. However, there stillremain problems in that the patients are unavoidable to visit thehospital twice or three times a week, that defects of erythrocyteproduction or maturation may occur, that complications will follow whichmay caused by the accumulation of aluminum and β2-microglobulin in abody occurring after the long-term dialysis, and so on.

The object of the present invention is to provide a therapeutic agentfor renal failure on which already-existing drugs or agents showunsatisfactory effects.

DISCLOSURE OF INVENTION

The present invention provides a therapeutic agent for renal failurecomprising, as an active ingredient, a 4,8-inter-m-phenyleneprostaglandin I₂ derivative or a pharmacologically acceptable saltthereof.

BEST MODE FOR CARRYING OUT THE INVENTION

The 4,8-inter-m-phenylene prostaglandin I₂ derivative according to thepresent invention is represented by the following formula (I):

wherein:R¹ represents:

-   -   (A) COOR²        -   wherein R² represents:        -   1) hydrogen or a pharmacologically acceptable positive ion;        -   2) a straight-chain C₁₋₁₂ alkyl group or a branched C₃₋₁₄            alkyl group;        -   3) -Z-R³            -   wherein Z represents a valence bond or a straight-chain                or branched alkylene group represented by C_(t)H_(2t)                where t represents an integer from 1 to 6; and R³                represents a C₃₋₁₂ cycloalkyl group unsubstituted or                substituted by 1 to 3 substituents of R⁴ where R⁴ is                hydrogen or a C₁₋₅ alkyl group;        -   4) —(CH₂CH₂O)CH₃            -   wherein n represents an integer from 1 to 5;        -   5) -Z-Ar¹            -   wherein Z has the same meaning as defined above; and Ar¹                represents phenyl, α-naphthyl, β-naphthyl, 2-pyridyl,                3-pyridyl, 4-pyridyl, α-furyl, β-furyl, α-thienyl,                β-thienyl or substituted phenyl (wherein the substituted                phenyl contains at least one substituent of chlorine,                bromine, fluorine, iodine, trifluoromethyl, a C₁₋₄ alkyl                group, nitro, cyano, methoxy, phenyl, phenoxy,                p-acetamidobenzamide, —CH═N—NH—C(═O)—NH₂, —NH—C(═O)-Ph,                —NH—C(═O)—CH₃ or —NH—C(═O)—NH₂);        -   6) —C_(t)H_(2t)COOR⁴            -   wherein each of C_(t)H_(2t) and R₄ has the same meaning                as defined above;        -   7) —C_(t)H_(2t)N(R⁴)₂            -   wherein each of C_(t)H_(2t) and R₄ has the same meaning                as defined above;        -   8) —CH(R⁵)—C(═O)—R⁶,            -   wherein R⁵ represents hydrogen or benzoyl; and R⁶                represents phenyl, p-bromophenyl, p-chlorophenyl,                p-biphenyl, p-nitrophenyl, p-benzamidophenyl or                2-naphthyl;        -   9) —C_(p)H_(2p)—W—R⁷            -   wherein W represents —CH═CH—, —CH═CR⁷— or —C≡C—; R⁷                represents hydrogen or a straight-chain or branched                C₁₋₃₀ alkyl or aralkyl group; and p represents an                integer from 1 to 5; or        -   10) —CH(CH₂OR⁸)₂            -   wherein R⁸ represents a C₁₋₃₀ alkyl or acyl group;    -   (B) —CH₂OH;    -   (C) —C(═O)N(R⁹)₂        -   wherein R⁹ represents hydrogen or a straight-chain C₁₋₁₂            alkyl group, a branched C₃₋₁₂ alkyl group, a C₃₋₁₂            cycloalkyl group, a C₄₋₁₃ cycloalkylalkylene group, a phenyl            group, a substituted phenyl group (wherein the substitute or            substituents are the same radicals as defined for (A)-5)            described above), a C₇₋₁₂ aralkyl group, or —SO₂R¹⁰ where            R¹⁰ represents a C₁₋₁₀ alkyl group, a C₃₋₁₂ cycloalkyl            group, a phenyl group, a substituted. phenyl group [wherein            the substitute or substituents are the same radicals as            defined for (A)-5] described above] or a C₇₋₁₂ aralkyl            group; provided that the two R⁹ radicals are the same as or            different from each other, but when one represents —SO₂R¹⁰,            then the other does not represent —SO₂R¹⁰; or    -   (D) —CH₂OTHP (wherein THP represents a tetrahydropyranyl group);        A represents:    -   1) —(CH₂)_(m)—;    -   2) —CH═CH—CH₂—;    -   3) —CH₂—CH═CH—;    -   4) —CH₂—O—CH₂—;    -   5) —CH═CH—;    -   6) —O—CH₂—; or    -   7) —C—C—        -   wherein m represents an integer from 1 to 3;            Y represents hydrogen, a C₁₋₄ alkyl group, chlorine,            bromine, fluorine, formyl, methoxy or nitro group;            B represents —X—C(R¹¹)(R¹²)OR¹³    -   wherein:        -   R¹¹ represents hydrogen or a C₁₋₄ alkyl group;        -   R¹³ represents hydrogen, a C₁₋₁₄ acyl group, a C₆₋₁₅ aroyl            group, tetrahydropyranyl, tetrahydrofuranyl, 1-ethoxyethyl            or t-butyl;        -   X represents:            -   1) —CH₂—CH₂—;            -   2) —CH═CH—; or            -   3) —C≡C—; and        -   R¹² represents:            -   1) a straight-chain C₁₋₁₂ alkyl group or a branched                C₃₋₁₄ alkyl group;            -   2) -Z-Ar                -   wherein Z has the same meaning as defined above; and                    Ar² represents phenyl, α-naphthyl, β-naphthyl, or at                    least one chlorine, bromine, fluorine, iodine,                    trifluoromethyl, a C₁₋₄ alkyl group, nitro, cyano,                    methoxy, phenyl or phenoxy-substituted phenyl, or            -   3) —C_(t)H_(2t)OR¹⁴;                -   wherein C_(t)H_(2t) has the same meaning as defined                    above; and R¹⁴ represents a straight-chain C₁₋₆                    alkyl group, a branched C₃₋₆ alkyl, phenyl, or at                    least one chlorine, bromine, fluorine, iodine,                    trifluoromethyl, an C₁₋₄ alkyl, nitro, cyano,                    methoxy, phenyl or phenoxy-substituted phenyl,                    cyclopentyl, cyclohexyl, or a cyclopentyl or                    cyclohexyl substituted by 1 to 4 straight-chain C₁₋₄                    alkyl groups;            -   4) -Z-R³                -   wherein each of Z and R³ has the same meaning as                    defined above;                -   5) —C_(t)H_(2t)—CH═C(R¹⁵)R¹⁶                -   wherein C_(t)H_(2t) has the same meaning as defined                    above; and R¹⁵ and R¹⁶ independently represent                    hydrogen, methyl, ethyl, propyl or butyl group; or            -   6) —C_(u)H_(2u)—C≡C—R¹⁷                -   wherein u represents an integer from 1 to 7;                    C_(u)H_(2u) represents a straight-chain or branched                    alkylene group; and R¹⁷ represents a straight-chain                    C₁₋₆ alkyl group; and            -   E represents hydrogen or —OR¹⁸    -   wherein R¹⁸ represents a C₁₋₁₂ acyl group, a C₇₋₁₅ aroyl group        or R² (wherein R² has the same meaning as defined above); and        the formula is in the isomeric d-form, 1-form or dl-form.

The therapeutic agent for renal failure according to the presentinvention comprises, as an active ingredient, a 4,8-inter-m-phenyleneprostaglandin I₂ derivative represented by the formula (I) above or apharmacologically acceptable salt thereof.

Among the 4,8-inter-m-phenylene prostaglandin I₂ derivatives describedabove, those derivatives described below and pharmacologicallyacceptable salt thereof are preferably used which are represented by theformula (I) above wherein:

R¹ represents COOR² wherein R² represents hydrogen or apharmacologically acceptable positive ion;

A represents:

-   -   1) —(CH₂)_(m)—; or    -   2) —CH₂—CH═CH—        -   wherein m represents an integer from 1 to 3;            Y represents hydrogen;            B represents —X—C(R¹¹)(R¹²)OR¹³    -   wherein each of R¹¹ and R¹³ represent hydrogen;    -   X represents:        -   1) —CH═CH—; or        -   2) —C≡C—; and    -   R¹² represents:        -   1) -Z-Ar²;        -   2) -Z-R³; or        -   3) —C_(u)H_(2u)—C≡C—R¹⁷            -   wherein Z represents a valence bond or a straight-chain                or branched alkylene group represented by C_(t)H_(2t)                where t represents an integer from 1 to 6; Ar²                represents phenyl, α-naphthyl, β-naphthyl, or at least                one chlorine, bromine, fluorine, iodine,                trifluoromethyl, a C₁₋₄ alkyl group, nitro, cyano,                methoxy, phenyl or phenoxy-substituted phenyl; R³                represents a C₃₋₁₂ cycloalkyl group; u represents an                integer from 1 to 7; C_(u)H_(2u) represents a                straight-chain or branched alkylene group; and R¹⁷                represents a straight-chain C₁₋₆ alkyl group; and                E represents —OH. A particularly preferable derivative                is beraprost sodium having the following formula.

The 4,8-inter-m-phenylene prostaglandin I₂ derivative of the presentinvention can be produced by any known process. For example, a compoundrepresented by the formula (I) above or a salt thereof may be producedaccording to the process described in Japanese Examined PatentApplication Publication No. 1-53672.

In the present invention, the 4,8-inter-m-phenylene prostaglandin I₂derivative can be administered at a dose of 0.001 to 1000 mg per adultsubject once to three times a day.

The therapeutic agent for renal failure of the present invention maycomprise the derivative alone or a combination of plural types of thederivatives and may be administered as is. Alternatively, thetherapeutic agent may be administered orally in the form of a solidpreparation containing an additive or additives shown below.

The causal disease of renal failure to be treated in the presentinvention may include all of the nephropathic diseases, such as primaryrenal diseases, nephropathies in systemic diseases, congenital renaldiseases, renal infections, nephropathies induced by any nephrotoxicsubstance and obstructive urinary diseases. Specific examples of thecausal disease include, but are not limited to, chronicglomerulonephritis, diabetic nephropathy, chronic pyelonephritis, acuteprogressive nephritis, gestosis, cystic kidney, nephrosclerosis,malignant hypertension, nephropathies accompanied by various collagendiseases such as SLE, amyloid kidney, gouty kidney, disbolic renalfailure, tuberculosis, renal calculosis, malignant tumor in the kidneyand urinary tracts, obstructive urinary tract diseases, myeloma andrenal hypoplasia.

The renal failure to be treated with the therapeutic agent of thepresent invention is not particularly limited to either of acute orchronic type. However, the therapeutic agent is especially effective onchronic renal failure for which no effective therapy has currently beenestablished and can delay the entrance into dialysis. Even when enteredinto dialysis, the therapeutic agent may be effective for thepreservation of functions of the remained kidney.

The additive may include excipients, such as starches, lactose, sucrose,glucose, mannitol, calcium carbonate and calcium sulfate; binders, suchas starches, dextrin, gum arabic, gum tragacanth, methyl cellulose,gelatin, polyvinyl pyrrolidone and polyvinyl alcohol; disintegratingagents, such as starches, polyvinyl pyrrolidone and crystallinecellulose; lubricants, such as magnesium stearate and talk; coloringagents; flavoring agents; and so on.

The 4,8-inter-m-phenylene prostaglandin I₂ derivative to be used in thepresent invention may be administered in various dosage forms.Specifically, the dosage form may be any conventional one, such astablets, dragees, powders, granules, troches, capsules, pills, syrup andspray.

The derivative may also be administered parentally in the form of asterile solution. Sodium chloride, glucose or any other solute may beadded to the solution, for example, in the amount sufficient to make thesolution isotonic.

In addition to the dosage form for oral administration mentioned above,the therapeutic agent for renal failure of the present invention may beprepared in various dosage forms, such as various types of injectionsand suppositories for parenteral administration.

EXAMPLES

The present invention will be described more in detail with reference tothe following examples.

Example 1

Effect of Beraprost Sodium on 5/6 Nephrectomized Rat Model:

The effect of beraprost sodium on a 5/6 nephrectomized rat model, whichhas been widely used as a model animal for renal failure, was examined.Two-thirds of the left kidney was removed from each of 4-week-old maleWistar rats (Charles River Japan Inc.) with a razor, and all of theright kidney was then removed therefrom one week after. Three weeksafter the initial surgery, blood was collected from each rat through thetail vein and serum creatinine and BUN levels were determined from theblood. At this point of time, the urine was also collected for 24 hoursto determine the mass of proteins in the urine. The rats were allocatedto one of the treatment groups by the stratifying continuousrandomization method based on the mass of proteins in the urine and thebody weight (n=8 per group). There was observed little difference in theinitial values of blood creatinine and BUN values among the rats. Threeweeks after the initial surgery, beraprost sodium or captopril (SIGMA,i.e., a positive control) was orally administered to each rat twice aday everyday, beginning the day on which administration of a drug wasstarted and continued through five weeks after the administration. Thedetermination of the renal functions was performed both three weeks andfive weeks after the initial administration of a drug. The photographicimages of the renal tissue were observed only five weeks after theinitial administration. In the sham surgery group (“sham”) in which nodrug was administered, increased BUN level (which is a measure of theprogress of chronic renal failure) was observed three weeks after theinitial administration, which indicated that chronic renal failure wasadvanced. Five weeks after the initial administration, more exacerbationof chronic renal failure was observed. In the beraprostsodium-administered group, significant prevention of increase in theurinary protein level and prevention of reduction in the creatinineclearance and increase in the BUN level were observed three weeks afterthe initial administration (Table 1). The same tendency was shown fiveweeks after the initial administration (Table 2). As demonstrated by theobservation of renal tissue images five weeks after the initialadministration, the progress of the glomerular conditions was markedlyprevented (Table 3). In the positive control group (i.e., thecaptopril-administered group), the similar ameliorative effects wereshown. These results clearly demonstrate that beraprost sodium canimprove the conditions of renal failure rats. TABLE 1 Effect ofberaprost on chronic renal failure model rats (three weeks after theadministration of a drug) Urinary Urinary protein Creatinine Blood ureaBody volume excretion clearance nitrogen Drug weight (g) (ml/24 hr)(mg/24 hr/kgBW) (μl/min/100 gBW) (μg/dl) Sham 229.4 ± 6.1 32.3 ± 3.7 3.6 ± 0.6 430.9 ± 15.3 14.9 ± 1.1 Control 224.8 ± 6.9 18.4 ± 1.7**320.6 ± 69.7** 132.7 + 19.9** 58.9 ± 7.7** Captopril 220.6 ± 5.4 21.7 ±3.7 136.8 ± 29.9 151.9 ± 12.3 51.4 ± 3.7 (50 mg/kg) TRK-100 215.5 ± 5.320.1 ± 2.8 125.3 ± 20.8^(#) 134.1 ± 11.0 55.9 ± 3.7 (100 μg/kg) TRK-100221.0 ± 6.3 20.4 ± 3.7 154.4 ± 53.0^(#) 136.4 ± 9.9 50.9 ± 3.6 (300μg/kg)Values represent mean ± s.e.m. from 8 rats.**represents the control group having a significant difference from thesham group (p < 0.01).^(#)(p < 0.05) and ## (p, 0.01) represent the drug-administered groupshaving a significant difference from the control group.

TABLE 2 Effect of beraprost on chronic renal failure model rats (fiveweeks after the administration of a drug) Urinary Urinary proteinCreatinine Blood urea Body volume excretion clearance nitrogen Drugweight (g) (ml/24 hr) (mg/24 hr/kgBW) (μl/min/100 gBW) (μg/dl) Sham238.4 ± 7.1 24.7 ± 4.1  7.8 ± 0.7 365.6 ± 20.1 16.9 ± 1.1 Control 237.2± 8.1 22.1 ± 3.6 301.4 ± 51.6** 135.4 ± 22.9** 55.2 ± 9.7** Captopril236.4 ± 5.7 21.9 ± 3.2 255.5 ± 76.6 161.1 ± 17.3 47.8 ± 5.2 (50 mg/kg)TRK-100 228.7 ± 5.7 21.7 ± 3.1 276.5 ± 69.2 156.9 ± 19.5 45.5 ± 3.3 (100μg/kg) TRK-100 245.8 ± 8.0 20.4 ± 1.7 197.1 ± 21.1 143.5 ± 10.0 45.1 ±3.5 (300 μg/kg)Values represent mean ± s.e.m. from 7-8 rats.**represents the control group having a significant difference from thesham group (p < 0.01).

TABLE 3 Captopril BPS BPS Region Histopathological change Sham Control(50 μg/kg) (100 μg/kg) (300 μg/kg) Renal corpuscle Glomerularhypertrophy 0 8 1 3 2 Cellular filling in glomerulus 0 7 4 7 4Glomerulosclerosis 0 3 2 2 1 Epidermal growth in Bowman's capsule 0 5 21 1 Deposition of PAS + materials in 0 3 1 2 1 Bowman's capsuleCoagulation of glomeruli in Bowman's 0 5 2 2 1 capsule UriniferousBasophilic degeneration of tubules 0 8 6 8 8 tuble Proliferation ofproximal tubules 0 8 8 8 8 Tubular dilation 0 8 8 8 8 Proteinaceousurinary casts 0 8 4 5 2 Framework Infiltration of mononuclear cells 0 67 7 7Each value represents the number of animals in which histopathologicalchange was observed in 8 animals per group.

Example 2

Renal failure rat models of which the primary disease wasglomerulonephritis were used to examine the effect of different4,8-inter-m-phenylene prostaglandin I₂ derivatives including beraprostsodium on the models. Eight-week-old male WKY rats (Charles River JapanInc.) were administered intravenously with rabbit anti-rat glomerularbasement membrane antiserum to induce glomerulonephritis. Two weeksafter the induction, blood was collected from each rat through the tailvein to determine blood creatinine and BUN levels. The blood creatinineand BUN levels in the glomerulonephritis-induced rats were remarkablyhigher than those in the non-induced rats, which indicated that theconditions of the rats progressed into renal failure. Four types of4,8-inter-m-phenylene prostaglandin I₂ derivatives in total, includingberaprost sodium, were individually administered subcutaneously to therats from the back continuously with an osmotic pump (ALZET) for oneweek, beginning two weeks after induction of glomerulonephritis andcontinued through three weeks after the induction. The renal functions(i.e., blood creatinine and BUN levels) were determined one week afterthe initial administration of a drug. In a glomerulonephritis-inducedgroup to which no drug was administered (i.e., a control group), bloodcreatinine and the BUN levels determined three weeks after the inductionof glomerulonephritis were increased compared with those determined twoweeks after the induction, which indicated that the conditions of therats progressed into chronic renal failure. In a beraprostsodium-administered group, blood creatinine and BUN levels determinedthree weeks after the induction of glomerulonephritis were significantlydecreased compared with those in the control group (Table 4). In groupsto which other three types of 4,8-inter-m-phenylene prostaglandin I₂derivatives (i.e., compounds 1, 2 and 3 shown below) were respectivelyadministered, the similar ameliorative effect was observed (Table 5).

These results indicate that the 4,8-inter-m-phenylene prostaglandin I₂derivatives including beraprost sodium can improve the conditions ofrats with renal failure. TABLE 4 Effect of beraprost sodium on renalfailure rat models of which the primary disease is glomerulonephritisBlood creatinine (mg/dl) BUN (mg/dl) 2 weeks 2 weeks after 3 weeks afterafter 3 weeks after induction induction induction induction (before (1week after (before (1 week after adminis- the initial adminis- theinitial tration) administration) tration) administration) Normal 0.32 ±0.02 0.30 ± 0.01 11 ± 1 18 ± 1 group Control 0.64 ± 0.09 * 0.89 ± 0.12 *33 ± 7 * 40 ± 3 * group Beraprost sodium-administered group 60 μg/kg0.61 ± 0.07 * 0.48 ± 0.04 # 28 ± 3 * 31 ± 2 # 200 μg/kg 0.62 ± 0.06 *0.49 ± 0.04 # 30 ± 3 * 25 ± 1 #* p < 0.05 vs. normal group (Student's t-test)#: p < 0.05 vs. control group (Dunnett method)

TABLE 5 Effect of different 4,8-inter-m-phenylene prostaglandin I₂derivatives on renal failure rat models of which the primary disease isglomerulonephritis Blood creatinine (mg/dl) BUN (mg/dl) 3 weeks 3 weeks2 weeks after induc 2 weeks after induc- after -tion (1 after tion (1induction week after induction week after (before the initial (beforethe initial adminis- adminis- adminis- adminis- tration) tration)tration) tration) Normal 0.30 ± 0.02 0.29 ± 0.02 19 ± 1 19 ± 1 groupControl 0.44 ± 0.03 * 0.65 ± 0.04 * 28 ± 2 * 44 ± 2 * group4,8-inter-m-phenylene prostaglandin I₂ derivative-administered groupCompound 1 0.44 ± 0.05 * 0.41 ± 0.02 # 29 ± 2 * 27 ± 2 # 60 μg/kgCompound 2 0.45 ± 0.04 * 0.44 ± 0.05 # 28 ± 2 * 31 ± 3 # 60 μg/kgCompound 3 0.45 ± 0.05 * 0.39 ± 0.04 # 28 ± 3 * 30 ± 3 # 60 μg/kg* p < 0.05 vs. normal group (Student's t-test)#: p < 0.05 vs. control group (Dunnett method)

Example 3

Glomerulonephritis rat models were used to examine the effect ofberaprost sodium on the rat models both in a stage where renal failurehad not been found (i.e., the inflammatory stage) and a stage where BUNlevel was increased and the conditions were progressed into renalfailure (i.e., the renal failure stage). Eight-week-old male WKY rats(Charles River Japan Inc.) were administered intravenously with rabbitanti-rat glomerular basement membrane antiserum to induceglomerulonephritis. Each of beraprost sodium, captopril (SIGMA) andprednisolone (Shionogi & Co., Ltd.) was orally administered to the ratseveryday either for one week from day 1 through day 7 after induction ofglomerulonephritis (i.e., during the inflammatory stage) or for twoweeks beginning two weeks after the induction through four weeks afterthe induction (i.e., during the renal failure stage). The frequency ofthe administration was twice a day for beraprost sodium and captopriland once a day for prednisolone. After the initial administration of adrug, urinary total protein excretion (which is a measure of renalfunctions) was determined. In the inflammatory stage (i.e., from day 1through day 7 after induction of glomerulonephritis), the urinary totalprotein excretion in a glomerulonephritis-induced group to which no drugwas administered (i.e., a control group) was remarkably increasedcompared with that in a non-glomerulonephritis-induced group (i.e., anormal group) (Table 6). In a beraprost sodium-administered group, theincrease in urinal total protein excretion was markedly prevented (Table6). In both captopril- and prednisolone-administered groups, effectiveprevention of increase in urinal total protein excretion was observed(Table 6). On the other hand, in the renal failure stage (i.e., from twoweeks after induction of glomerulonephritis through four weeks after theinduction), the urinary total protein excretion in theglomerulonephritis-induced group without administration of a drug (i.e.,the control group) was remarkably increased compared with that in anon-glomerulonephritis-induced group (i.e., a normal group); incontrast, in the beraprost sodium-administered group, the increase inurinal total protein excretion was markedly prevented (Table 6). In boththe captopril- and prednisolone-administered groups, no effectiveprevention of increase in urinal total protein excretion was observed(Table 6).

These results indicate that both prednisolone and captopril are noteffective on the rats in the renal failure stage although they areeffective on the rats in the inflammatory stage. In contrast, it isclearly indicated that beraprost sodium can improve the conditions ofthe rats both in the inflammatory stage and the renal failure stage.TABLE 6 Effect of beraprost sodium, captopril and prednisolone onglomerulonephritis model rats in inflammatory and renal failure stagesUrinary total protein excretion (mg/24 hr) Renal failure stageInflammatory stage Exp. 1 Exp. 2 7 days after 3 weeks after 4 weeksafter induction 2 weeks after induction 2 weeks after induction (1 weekafter induction (1 week after induction (2 week after initial (beforeinitial (before initial administration administration) administration)administration) administration) Normal group  19 ± 1  30 ± 6  20 ± 2  14± 1  17 ± 1 Control group 138 ± 9* 370 ± 30* 423 ± 55* 324 ± 18* 451 ±77* Beraprost-administered group 300 μg/kg  17 ± 7# 374 ± 21* 300 ± 51#321 ± 23* 295 ± 46# Captopril-administered group 50 mg/kg  75 ± 14# N.D.N.D. 318 ± 22* 504 ± 51 100 mg/kg N.D. N.D. N.D. 325 ± 6* 517 ± 33Prednisolone-administered group 2 mg/kg  38 ± 8# 368 ± 20 456 ± 78 N.D.N.D.*p < 0.05 vs. normal group (Student's t-test)#: p < 0.05 vs. control group (Dunnett method)N.D.: Not determined.

INDUSTRIAL APPLICABILITY

The present invention provides a therapeutic agent for renal failurecomprising, as an active ingredient, a 4,8-inter-m-phenyleneprostaglandin I₂ derivative.

1-10. (canceled)
 11. A method for treatment of chronic renal failurecomprising administering a therapeutically effective amount of a4,8-inter-m-phenylene prostaglandin I₂ derivative represented by thefollowing formula (I) or a pharmacologically acceptable salt thereof:

wherein: R¹ represents: (A) COOR² wherein R² represents: 1) hydrogen ora pharmacologically acceptable positive ion; 2) a straight-chain C₁₋₁₂alkyl group or a branched C₃₋₁₄ alkyl group; 3) -Z-R³ wherein Zrepresents a valence bond or a straight-chain or branched alkylene grouprepresented by C_(t)H_(2t) where t represents an integer from 1 to 6;and R³ represents a C₃₋₁₂ cycloalkyl group unsubstittued or substitutedby 1 to 3 substituents of R⁴ where R⁴ is hydrogen or a C₁₋₅ alkyl group;4) —(CH₂CH₂O)_(n)CH₃ wherein n represents an integer from 1 to 5; 5)-Z-Ar¹ wherein Z has the same meaning as defined above; and Ar¹represents phenyl, α-naphthyl, β-naphthyl, 2-pyridyl, 3-pyridyl,4-pyridyl, α-furyl, β-uryl, α-thienyl, β-thienyl or substituted phenyl(wherein the substituted phenyl contains at least one substituent ofchlorine, bromine, fluorine, iodine, trifluoromethyl, a C₁₋₄ alkylgroup, nitro, cyano, methoxy, phenyl, phenoxy, p-acetamidobenzamide,—CH═N—NH—C(═O)—NH₂, —NH—C(═O)-Ph, —NH—C(═O)—CH₃ or —NH—C(═O)—NH₂); 6)—C_(t)H_(2t)COOR⁴ wherein each of C_(t)H_(2t) and R⁴ has the samemeaning as defined above; 7) —C_(t)H_(2t)N(R⁴)₂ wherein each ofC_(t)H_(2t) and R⁴ has the same meaning as defined above; 8)—CH(R⁵)—C(═O)—R⁶ wherein R⁵ represents hydrogen or benzoyl; and R⁶represents phenyl, p-bromophenyl, p-chlorophenyl, p-biphenyl,p-nitrophenyl, p-benzamidophenyl or 2-naphthyl; 9) —C_(p)H_(2p)—W—R⁷wherein W represents —CH═CH—, —CH═CR⁷— or —C═C—; R⁷ represents hydrogenor a straight-chain or branched C₁₋₃₀ alkyl or araalkyl group; and prepresents an integer from 1 to 5; or 10) —CH(CH₂OR⁸)₂ wherein R⁸represents a C₁₋₃₀ alkyl or acyl group; (B) —CH₂OH; (C) —C(═O)N(R⁹)₂wherein R⁹ represents hydrogen or a straight-chain C₁₋₁₂ alkyl group, abranched C₃₋₁₂ alkyl group, a C₃₋₁₂ cycloalkyl group, a C₄₋₁₃cycloalkylalkylene group, a phenyl group, a substituted phenyl group(wherein the substitute or substituents are the same radicals as definedfor (A)-5) described above), a C₇₋₁₂ aralkyl group, or —SO₂R¹⁰ where R¹⁰represents a C₁₋₁₀ alkyl group, a C₃₋₁₂ cycloalkyl group, a phenylgroup, a substituted phenyl group (wherein the substitute orsubstituents are the same radicals as defined for (A)-5) describedabove) or a C₇₋₁₂ aralkyl group; provided that the two R⁹ radicals arethe same as or different from each other, but when one represents—SO₂R¹⁰, then the other does not represent —SO₂R¹⁰; or (D) —CH₂OTHP(wherein THP represents a tetrahydropyranyl group); A represents: 1)—(CH₂)_(m)—; 2) —CH═CH—CH₂—; 3) —CH₂—CH═CH—; 4) —CH₂—O—CH₂—; 5) —CH═CH—;6) —O—CH₂—; or 7) —C═C— wherein m represents an integer from 1 to 3; Yrepresents hydrogen, a C₁₋₄ alkyl group, chlorine, bromine, fluorine,formyl, methoxy or nitro group; B represents —X—C(R¹¹)(R¹²)OR¹³ wherein: R¹¹ represents hydrogen or a C₁₋₄ alkyl group; R¹³ represents hydrogen,a C₁₋₁₄ acyl group, a C₆₋₁₅ aroyl group, tetrahydropyranyl,tetrahydrofuranyl, 1-ethoxyethyl or t-butyl; X represents: 1) —CH₂—CH₂—;2) —CH═CH—; or 3) —C═C—; and R¹² represents: 1) a straight-chain C₁₋₁₂alkyl group or a branched C₃₋₁₄ alkyl group; 2) -Z-Ar²  wherein Z hasthe same meaning as defined above; and Ar² represents phenyl,α-naphthyl, β-naphthyl, or at least one chlorine, bromine, fluorine,iodine, trifluoromethyl, a C₁₋₄ alkyl group, nitro, cyano, methoxy,phenyl or phenoxy-substituted phenyl, or 3) —C_(t)H_(2t)OR¹⁴  whereinC_(t)H_(2t) has the same meaning as defined above; and R¹⁴ represents astraight-chain C₁₋₆ alkyl group, a branched C₃₋₆ alkyl, phenyl, or atleast one chlorine, bromine, fluorine, iodine, trifluoromethyl, a C₁₋₄alkyl, nitro, cyano, methoxy, phenyl or phenoxy-substituted phenyl,cyclopentyl, cyclohexyl, or a cyclopentyl or cyclohexyl substituted by 1to 4 straight-chain C₁₋₄ alkyl groups; 4) -Z-R³  wherein each of Z andR³ has the same meaning as defined above; 5) —C_(t)H_(2t)—CH═C(R¹⁵)R¹⁶ wherein C_(t)H_(2t) has the same meaning as defined above; and R¹⁵ andR¹⁶ independently represent hydrogen, methyl, ethyl, propyl or butylgroup; or 6) —C_(u)H_(2u)—C═C—R¹⁷  wherein u represents an integer from1 to 7; C_(u)H_(2u) represents a straight-chain or branched alkylenegroup; and R¹⁷ represents a straight-chain C₁₋₆ alkyl group; and Erepresents hydrogen or —OR¹⁸ wherein R¹⁸ represents a C₁₋₂ acyl group, aC₇₋₁₅ aroyl group or R² (wherein R² has the same meaning as definedabove); and the formula (I) is in the isomeric d-form, l-form ordl-form.
 12. The method for treatment of chronic renal failure accordingto claim 11, wherein the 4,8-inter-m-phenylene prostaglandin I₂derivative is represented by the following formula (I):

wherein: R¹ represents COOR² wherein R² represents hydrogen or apharmacologically acceptable positive ion; A represents: 1) —(CH₂)_(m)—;or 2) —CH₂—CH═CH— wherein m represents an integer from 1 to 3; Yrepresents hydrogen; B represents —X—C(R¹¹)(R¹²)OR¹³ wherein each of R¹¹and R¹³ represent hydrogen; X represents: 1) —CH═CH—; or 2) —C═C—; andR¹² represents: 1) -Z_Ar²; 2) -Z-R³; or 3) —C_(u)H_(2u)—C═C—R¹⁷ whereinZ represents a valence bond or a straight-chain or branched alkylenegroup represented by C_(t)H_(2t) where t represents an integer from 1 to6; Ar² represents phenyl, α-naphthyl, β-naphthyl, or at least onechlorine, bromine, fluorine, iodine, trifluoromethyl, a C₁₋₄ alkylgroup, nitro, cyano, methoxy, phenyl or phenoxy-substituted phenyl; R³represents a C₃₋₁₂ cycloalkyl group; u represents an integer from 1 to7; C_(u)H_(2u) represents a straight-chain or branched alkylene group;and R¹⁷ represents a straight-chain C₁₋₆ alkyl group; E represents —OH;and the formula (I) is in the isomeric d-form, l-form or dl-form. 13.The method according to claim 11, wherein the 4,8-inter-m-phenyleneprostaglandin I₂ derivative is beraprost or a salt thereof.
 14. Themethod according to claim 11, wherein the causal disease of the chronicrenal failure is glomerulonephritis, nephrosclerosis or diabeticnephropathy.
 15. The method according to claim 11, wherein said chronicrenal failure is defined by raise of serum creatinine level and/or bloodurea nitrogen level.
 16. The method according to claim 11, wherein saidchronic renal failure is progressive chronic renal failure in whichserum creatinine level and/or blood urea nitrogen level raise(s) withtime.
 17. The method according to claim 11, wherein increase in serumcreatinine level and/or blood nitrogen level is(are) reduced, or t5heserum creatinine level and/or blood urea nitrogen level is(are)decreased.